Crystalline phases of 5,6-dichloro-2-(isopropylamino)-(1-beta-l-ribofuranosyl)-1h-benzimidazole

ABSTRACT

The invention relates to novel crystalline phases of 5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole (Maribavir), pharmaceutical compositions thereof and their use in medical therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 13/282,510, filed Oct. 27, 2011, which claims the benefit ofU.S. Provisional Patent Application No. 61/407,622, filed Oct. 28, 2010,the entire disclosures of which are incorporated by reference herein.

BACKGROUND OF THE INVENTION

The present invention relates to an unsolvated crystalline form, varioussolvates, and the HCl monohydrate salt of the antiviral compound5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(also known as 1263W94; maribavir; a compound of formula (I) below),pharmaceutical formulations comprising such crystalline form, solvatesand the HCl monohydrate, and their use in therapy.

5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(1263W94; maribavir) is a benzimidazole derivative useful in medicaltherapy. U.S. Pat. No. 6,077,832 discloses5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazoleand its use for the treatment or prophylaxis of viral infections such asthose caused by herpes viruses. The compound as disclosed in U.S. Pat.No. 6,077,832 is an amorphous, non-crystalline material.

The structure of5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole,a compound of formula (I) is shown below:

The preparation of certain crystalline forms and solvate forms of5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole,as well as pharmaceutical formulations thereof and their use in therapyare described in U.S. Pat. Nos. 6,469,160 and 6,482,939.

Different polymorphs normally have different solubilities, differentresidence times in the body and different therapeutic values. In view ofthese differences, it is important in drug development to determine theproperties, and control, to the extent possible, the presence ofpolymorphs in any drug product administered in crystalline form that issubmitted for regulatory approval.

SUMMARY OF THE INVENTION

It has now been discovered, in accordance with this invention, that5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(1263W94; maribavir) may be prepared in a novel unsolvated crystallineform, solvate forms and as the HCl monohydrate salt in addition to thosepreviously described.

According to one aspect of the invention there is provided the compoundof formula (I) in a novel crystalline form, Form VII. Form VII isdefined by the X-ray powder diffraction pattern (XRPD) illustrated inFIG. 1, the DSC profile illustrated in FIG. 2 and the IR spectrum inFIG. 3, which is obtained in the manner described in the examples thatfollow.

In another aspect of the invention various solvates of the compound offormula (I) and the hydrochloride are provided, which are selected fromthe group of methanol, acetonitrile, ethyl acetate, diethylether,n-butylacetate, 1-propanol solvates, hydrochloride monohydrate ormixtures thereof. These phases, which are defined by their respectiveX-ray powder diffraction patterns, illustrated in FIGS. 2 to 8, areobtained using the procedures exemplified below.

In still with another aspect of the present invention, pharmaceuticalcompositions are provided comprising one or more of the polymorphsdescribed herein and one or more pharmaceutically acceptable carriersand/or excipients. Suitable carriers and excipients for the formulationof pharmaceutically acceptable compositions comprising the polymorphs ofthis invention are well known in the art and are disclosed, for example,in U.S. Pat. No. 6,077,832.

The present invention also provides a method for the treatment orprophylaxis of a viral infection, particularly a herpes infection, suchas cytomegalovirus (CMV) infection, as well as disease caused byhepatitis B and hepatitis C viruses in a patient, e.g. a mammal such asa human, which comprises administering to the patient an effectiveantiviral amount of the compound of formula (I) as unsolvatedcrystalline Form VII or a novel solvate of such compound or the HClmonohydrate salt.

The present invention also provides the use of the compound of formula(I) anhydrous crystalline forms and solvates in the preparation of amedicament for the treatment or prophylaxis of a viral infection.

In a further aspect of the invention, there is provided the compound offormula (I) as a mixture of any two or more of the unsolvatedcrystalline form, VII, and/or solvates, and/or the HCl monohydrate saltdescribed herein, or as a mixture with amorphous material or with one ormore of the anhydrate crystalline forms and/or solvates previouslydescribed.

The novel crystalline form solvates, and the HCl monohydrate salt of thepresent invention are new crystalline phases of the compound5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazolethat have different chemical and/or physical properties relative knowncrystalline phases of the compound. For example, Form VII has arelatively low melting point. The ethyl acetate solvate can be isolateddirectly from the mother ethyl acetate liquor and can be used as anintermediate in the preparation of purified Form VI via a desolvationprocess. Depending on the desolvation conditions, the Form VII may (maynot) be formed as an intermediate during preparation of Form VI from theethyl acetate solvate. Purified Form VI may also be prepared by similarprocesses of desolvation with the corresponding diethyl ether solvate.The novel crystalline form and solvates described herein, which arecharacterized by their X-ray powder diffraction patterns,thermogravimetric analysis (TGA) and differential scanning calorimetry(DSC) profiles and IR spectra, can be produced in various conventionalsolid and liquid suspension dose forms for therapeutic use in the mannerpreviously described in U.S. Pat. Nos. 6,469,160 and 6,482,939.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A sets forth identifying data for Form VII of the compound ofFormula I, above, including X-ray powder diffraction pattern;

FIG. 1B sets forth identifying data for Form VII of the compound ofFormula I, above, including DSC profile;

FIG. 1C sets forth identifying data for Form VII of the compound ofFormula I, above, including IR spectrum;

FIG. 2 sets forth identifying data for methanol solvate of the compoundof Formula I, above, including 2A, X-ray powder diffraction pattern at20° C.; and 2B, temperature resolved X-ray powder diffraction patterns,the X-ray powder diffraction patterns being obtained using adiffractometer equipped with a Ni Filter in order to remove most part ofthe CuKβ radiation;

FIG. 3 sets forth identifying data for acetonitrile solvate of thecompound of Formula I, above, including 3A, X-ray powder diffractionpattern at 20° C. and 3B, temperature resolved X-ray powder diffractionpatterns, the X-ray powder diffraction pattern being obtained using adiffractometer equipped with a Ni Filter in order to remove most part ofthe CuKβ radiation;

FIG. 4 sets forth identifying data for ethyl acetate solvate of thecompound of Formula I, above, including, 4A X-ray powder diffractionpattern at 20° C.; and 4B, temperature resolved X-ray powder diffractionpatterns, the X-ray powder diffraction pattern being obtained using adiffractometer equipped with a Ni Filter in order to remove most part ofthe CuKβ radiation;

FIG. 5 sets forth identifying data for diethyl ether solvate of thecompound of Formula I, above, including, 5A X-ray powder diffractionpattern at 20° C.; and 5B, temperature resolved X-ray powder diffractionpatterns, the X-ray powder diffraction pattern being obtained using adiffractometer equipped with a Ni Filter in order to remove most part ofthe CuKβ radiation;

FIG. 6 sets forth identifying data for n-butyl acetate solvate of thecompound of Formula I, above, including X-ray powder diffraction patternat 20° C., the X-ray powder diffraction pattern being obtained using adiffractometer equipped with a Ni Filter in order to remove most part ofthe CuKβ radiation;

FIG. 7 sets forth identifying data for 1-propanol solvate of thecompound of Formula I, above, including X-ray powder diffraction patternat 20° C., the X-ray powder diffraction pattern being obtained using adiffractometer equipped with a Ni Filter in order to remove most part ofthe CuKβ radiation;

FIG. 8 sets forth identifying data for monohydrate hydrochloride of thecompound of Formula I, above, including 8A X-ray powder diffractionpattern at 20° C., the X-ray powder diffraction pattern being obtainedusing a diffractometer equipped with a Ni Filter in order to remove mostpart of the CuKβ radiation; and 8B the TGA-DSC curve; and

FIG. 9 is an ORTEP drawing of the asymmetric unit of Form VI in the Lconfiguration. All non-H atoms are represented by their displacementellipsoids drawn at the 50% probability level. H atoms are displayedwith an arbitrary radius.

DETAILED DESCRIPTION OF THE INVENTION

“Polymorph”, as generally understood, refers to a solid phase of acompound which occurs in several distinct forms due to differentarrangements and/or confirmations of its molecular crystal lattice. Asused herein, the term “polymorph” includes solid phases resulting frompacking polymorphism and conformational polymorphism, and therefore mayinclude different unsolvated crystal forms of a compound, and mayinclude the crystalline forms made by removing the solvent from asolvate.

In particular embodiments of the present invention, pure, singlepolymorphs as well as mixtures comprising two or more differentpolymorphs are contemplated. A pure, single polymorph may besubstantially free from other polymorphs. “Substantially free”, as usedherein, signifies that other polymorph(s) are present in an amount lessthan about 10 weight percent, more preferably less than about 1 weightpercent and most preferably less than about 0.5 weight percent.

Additional technical terms used to describe the present invention, andtheir meanings, are provided below.

Crystalline phase (material): is a solid substance in which the atoms,molecules or ions are arranged in an orderly repeated pattern extendingin all three spatial dimensions (called crystal lattice) that givediffraction peaks when exposed to X-rays.

Amorphous phase (material): is a solid or semi-solid substance thatunlike the crystalline phase has no long range order of molecularpacking or well-defined molecular conformation if the molecules areconformationally flexible.

Form: is a crystalline phase of a substance without solvent or water ofcrystallization contained in the crystal lattice that possesses distinctarrangements and/or conformations of the molecules in the crystallattice detectable by X-ray powder diffraction pattern (XRPD) and singlecrystal X-ray crystallography among other techniques (that is,spectroscopic techniques).

Forms with cavities: forms that contain cavities, channels or voidspaces (all of which are referred to here as cavities) in the crystallattice. These forms may contain solvents and/or water in stoichiometricor non-stoichiometric amounts in the cavities.

Anhydrate (polymorph): a form with no water of crystallization in thecrystal lattice; residual surface water not making up part of thecrystal lattice might be present (some residual minor surface water maybe present).

Asolvate—Anhydrate (polymorph): a form with no solvent and/or water ofcrystallization in the crystal lattice; residual surface solvent and/orwater not making part of the crystal lattice might be present.

Anhydrous (polymorph): a form with no water of crystallization in thecrystal lattice and also no residual surface water.

Asolvate—Anhydrous (polymorph): a form with no solvent and/or water ofcrystallization in the crystal lattice and also no residual surfacesolvent and/or water.

Solvate: a crystallized phase that contains molecules of the solvent ofcrystallization in a stoichiometric and/or non-stoichiometric amount inthe crystal lattice. The solvent of crystallization may be water inwhich case the solvate is aptly referred to as “hydrate.” Astoichiometric solvate contains a discrete amount of solvent relative tothe compound molecule in the crystal structure. A non-stoichiometricsolvate contains in the crystal lattice a non-discrete or continuouschange in the solvent stoichiometry relative to the compound molecules.

Hydrate: a solvate in which the solvent of crystallization contained inthe crystal lattice is water. Similar to solvates, hydrates can bestoichiometric or non-stoichiometric.

Mixed hydrate/solvate: solvate in which the solvents of crystallizationcontained in the crystal lattice are both solvent and water. Mixedhydrates/solvates can be stoichiometric and/or non-stoichiometric.

Isomorphic solvates: are solvates that possess similar crystal structureproperties (same symmetries and similar unit cell parameters and crystalpacking) while having different chemical compositions (i.e., differentsolvent and/or water molecules incorporated in the crystal lattice). Theunit cell parameters of the isomorphic solvates within a class candiffer as a function of the size of the incorporated solvent. Thesolvent molecules of an isomorphic solvate can be hydrogen bonded to theparent molecule and/or contained in the cavities of the crystalstructure (also called a void space or channel).

Isomorphous desolvate: crystallized phase that does not contain solventor water anymore but whose structure is very similar to that of theformer solvate or hydrate.

Molecular ratio: the molecular ratio in a solvate of solvent moleculesrelative to the compound molecules in the crystal structure. Dependingon the solvate, the molecular ratio of in the crystal structure may beeither a stoichiometric ratio, e.g., a molecular ratio of 1:1, or anon-stoichiometric ratio.

The X-ray powder diffraction pattern of crystalline form VII, thevarious solvates and the HCl monohydrate salt of the present inventioncan be determined using conventional techniques and equipment known tothose skilled in the art of physical characterization. The diffractionpatterns of FIGS. 1A, and 2-8 were obtained with a Siemens D5005diffractometer system equipped with a Ni Filter in order to remove mostpart of the CuKβ radiation and a scintillator detector. The powdersample used to generate the X-ray powder diffraction data was preparedby conventional preparation techniques and deposited on the sampleholder of the TTK 450 chamber (anton Paar—Austria) This chamber and itsregulation hardware were used for temperature resolved XRPD analyses.Zero theta was checked by using Siemens calibrating slits.

A powder sample of Form VII, the various novel solvates, and the HClmonohydrate salt mentioned above was used to produce the X-ray powderdiffraction patterns of FIGS. 1A and 2-8, respectively. Form VII andeach of the novel solvates exhibit a diffraction pattern with a uniqueset of diffraction peaks which can be expressed in 2 theta angles(.degree.) or d-spacings (.ANG.) and relative peak intensities.

2 Theta diffraction angles and corresponding d-spacing values accountfor positions of various peaks in the X-ray powder diffraction pattern.D-spacing values are calculated with observed 2 theta angles and meancopper K.alpha. wavelength using the Bragg equation. Slight variationsin observed 2 theta angles and d-spacings are expected based on thespecific diffractometer employed and the analyst's sample preparationtechnique. Greater variation is expected for the relative peakintensities. Identification of the exact crystal form of a compoundshould be based primarily on observed 2 theta angles or d-spacings withlesser importance placed on relative peak intensities. In a mixture ofcrystal forms, the strongest diffraction peak for each form may overlapwith the diffraction peak of another form. In a mixture of crystalforms, identification may be based on the presence of a lesser intensitypeak that does not overlap with the other crystal forms.

Each of the unsolvated crystalline Form VII and/or solvates and/or HClmonohydrate salt of5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazolecan also be identified by the presence of multiple characteristic 2theta angle peaks including two, three, four, five, six, seven, eight,nine, or ten of the 2 theta angles which are reasonably characteristicof the particular crystalline form.

Some margin of error may be present in each of the 2 theta angleassignments and d-spacings reported herein. The error in determiningd-spacings decreases with increasing diffraction scan angle ordecreasing d-spacing. The margin of error in the 2 theta angles reportedin the following examples for Form VII, the various solvates and the HClmonohydrate salt is approximately ±0.1 degrees for each peak assignment.

Since some margin of error is possible in the assignment of 2 thetaangles and d-spacings, the preferred method of comparing X-ray powderdiffraction patterns in order to identify a particular crystalline formis to overlay the X-ray powder diffraction pattern of the newlydiscovered form over the X-ray powder diffraction pattern of a knownform. For example, one skilled in the art can overlay on FIG. 1A anX-ray powder diffraction pattern of an unidentified crystalline form of5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole,obtained using the methods described herein, and readily determinewhether the X-ray diffraction pattern of the unidentified form issubstantially the same as the X-ray powder diffraction pattern of FormVII. If the X-ray powder diffraction pattern is substantially the sameas FIG. 1A, the previously unknown crystalline form can be readily andaccurately identified as Form VII. The same technique can be used todetermine if an unidentified crystalline form is any of the solvateforms of5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazoledescribed herein by overlaying the X-ray powder diffraction pattern overFIGS. 2-8, respectively.

Although 2 theta angles or d-spacings are the primary method ofidentifying a particular crystalline form, it may be desirable to alsocompare relative peak intensities. As noted above, relative peakintensities may vary depending upon the specific diffractometeremployed, the shape of the crystals (the so-called ‘preferentialorientation effect’), the crystal size distribution, the quality of thelong range order (i.e. the crystallinity) and the analyst's samplepreparation technique. The peak intensities are reported as intensitiesrelative to the peak intensity of the strongest peak. The intensityunits on the X-ray diffraction plot are counts/sec.

Other methods of physical characterization can also be employed toidentify the unsolvated crystalline forms or solvates or the HClmonohydrate salt of the present invention. For example, melting point,differential scanning calorimetry and infrared spectra, are alltechniques known to those skilled in the art to be useful for thephysical characterization of a crystalline form or solvate. Thesetechniques may be employed alone or in combination to characterize agiven anhydrous crystalline form or solvate.

The present invention expressly contemplates mixtures of any of theforegoing unsolvated crystalline form or solvates or the HCl monohydratesalt with one or more of the amorphous compound of formula (I), and/orother anhydrous crystalline forms and solvates previously described. Itshould be understood that admixtures of a particular crystalline form orsolvate with amorphous compound of formula (I) and/or other crystallineforms or solvates may result in the masking or absence of one or more ofthe foregoing X-ray powder diffraction peaks described above for thatparticular form. Methods are known in the art for analyzing suchadmixtures of crystalline forms in order to provide for the accurateidentification of the presence or absence of particular crystallineforms in the admixture.

In addition to the foregoing, any of the unsolvated crystalline forms orsolvates of the present invention may be in admixture with hydratedcrystalline forms. For example in any batch containing the unsolvatedcrystalline compound of formula (I), there may also be hydratedcrystalline forms of the compound or its hydrochloride monohydrate saltform.

The crystalline Form VII, the solvate forms, and the HCl monohydratesalt of the compound of formula (I) described herein are useful asintermediate material(s) for the preparation of active pharmaceuticalingredients (API) and/or drug products that contain the compound offormula (I).

As previously mentioned, crystalline Form VII and the solvate forms ofthe compound of formula (I) as well as the hydrochloride monohydratedescribed herein are useful in medical therapy, for example in thetreatment or prophylaxis of a viral disease in a patient in needthereof, e.g. a mammal such as a human. The compound of formula (I)unsolvated crystalline Form VII and the solvates of such compounddescribed herein are especially useful for the treatment or prophylaxisof viral diseases such as herpes virus infections, for example, CMVinfections, as well as disease caused by hepatitis B and hepatitis Cviruses. In addition to its use in human medical therapy, the compoundof formula (I) anhydrous crystalline forms and solvates can beadministered to other patients for treatment or prophylaxis of viraldiseases, for example to other mammals.

As used herein, the term prophylaxis includes the prevention ofinfection, the prevention of occurrence of symptoms and the preventionof recurrence of symptoms.

Appropriate amounts of the polymorphs described herein foradministration in the treatment or prophylaxis of herpes viral infectionare essentially the same as described in U.S. Pat. Nos. 6,469,160 and6,482,939, which also describe suitable dose forms and routes ofadministration.

The novel crystalline form, solvates, and the HCl monohydrate salt ofthe invention can be administered conveniently in powder, tablet,capsule or suspension form.

Form VI has been described as the most thermodynamically stable form of5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole.The unit cell parameters and space group were stated in U.S. Pat. No.6,482,939 to be a=b=9.1542 A, c=41.687 Å with P4₃2₁2 (data recorded at160 K).

The research leading up to the preparation of the polymorphs describedherein involved a careful reexamination of the crystal structure andmore especially of the Flack parameter, which led the present inventorsto conclude without any doubt that the ribofuranosyl derivativecrystallized in the P4₁2₁2 space group, and not in the P4₃2₁2 spacegroup, as previously described. Single crystals suitable for X-rayanalysis were obtained by crystallization from ethyl acetate solution at323 K. The structure was solved in the tetragonal system with theenantiomorphic space group P4₁2₁2. The refinement led to a R₁ factor of0.02 (F²>2σ(F²)) with a Flack parameter of −0.02 (7). When using theP4₃2₁2 space group, a Flack parameter of 1.03 (7) with a similar R₁factor was obtained. The ORTEP view in FIG. 12 presents the asymmetricunit of Form VI having the L configuration. The latter configuration isstabilized by intramolecular hydrogen bonds given in Table 9B. Moreover,several Intermolecular H bonds contribute to the structural cohesion.The main interactions are given in Table 9C. No C1-C1 distance was foundshorter than 4 Å. Representativeness of the single crystal withreference to the raw Form VI was also confirmed. The single crystalX-ray diffraction analysis used to make the space group determination isset forth below in the examples.

The following examples describe the invention in further detail. Theseexamples are provided for illustrative purposes only, and should in noway be considered as limiting the invention.

EXAMPLE 1 Form VII

In a vial, 2.0 g of the5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(crystallized as form VI) were dissolved in 10.0 g of ethyl acetate atroom temperature. The solution was completely evaporated under anitrogen flux during five days. A crystalline powder was obtained. TheX-ray powder diffraction pattern of this powder is presented in FIG. 1A.Table 1 below gives the most significant XRPD peaks. The DSC curve ispresented in FIG. 1B and the IR spectrum is presented in FIG. 1C.

TABLE 1 XRPD pattern of form VII Angle d value Intensity Intensity %2-Theta ° Angstrom Count % 7.090 12.4583 2858 100 10.907 8.1050 465 1612.572 7.0351 415 15 13.200 6.7020 561 20 14.321 6.1795 628 22 14.7306.0088 415 15 16.613 5.3318 540 19 17.129 5.1725 611 21 17.489 5.06681735 61 18.549 4.7795 798 28 19.339 4.5860 769 27 21.532 4.1236 990 3522.384 3.9685 231 8 23.140 3.8405 389 14 23.655 3.7580 1486 52 24.9143.5709 334 12 25.361 3.5090 243 9 26.461 3.3656 277 10 27.472 3.2439 28110 28.671 3.1110 294 10 29.177 3.0582 430 15

EXAMPLE 2 Methanol Solvate

In a vial, 0.25 g of the5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(crystallized as form VI) were dissolved in 0.57 g of methanol at roomtemperature. The solid was completely dissolved into the solvent, andafter 15 minutes, a solid recrystallized. The suspension was filtratedgently under vacuum with a glass filter (porosity 3). The X-ray powderdiffraction pattern of this powder is presented in FIG. 2A. The behaviorof that solvate under heating has been monitored by using TR-XRPD. FIG.2B shows that after desolvation the solid is poorly crystallized, i.e.,close to being amorphous.

TABLE 2 Characteristic XRPD peaks of maribavir Methanol solvate Angle dvalue Intensity Intensity % 2-Theta ° Angstrom Count % 7.212 12.24743599 100 8.926 9.8990 1311 36 11.433 7.7332 801 22 12.689 6.9705 747 2113.782 6.4202 991 28 14.073 6.2879 919 26 14.631 6.0493 663 18 15.2165.8182 882 25 15.510 5.7084 673 19 16.846 5.2586 986 27 17.740 4.99541044 29 20.121 4.4095 567 16 20.873 4.2523 1440 40 21.140 4.1991 1384 3921.775 4.0782 559 16 22.003 4.0364 544 15 23.039 3.8571 1050 29 23.2173.8280 884 25 23.960 3.7109 562 16 24.304 3.6592 511 14 25.625 3.47352110 59 26.032 3.4201 897 25 26.314 3.3840 627 17 27.289 3.2653 1510 4227.600 3.2292 861 24 27.828 3.2033 841 23 28.436 3.1362 584 16 28.7523.1025 879 24

EXAMPLE 3 Acetonitrile Solvate

In a vial, 0.20 g of the5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(crystallized as form VI) were dissolved in 2.77 g of acetonitrile atroom temperature. The solid was completely dissolved into the solvent,and after 2 minutes, a solid recrystallized. The suspension wasfiltrated gently under vacuum with a glass filter (porosity 3). TheX-ray powder diffraction pattern of this powder is presented in FIG. 3A.

TABLE 3 Characteristic XRPD peaks of maribavir Acetonitrile solvateAngle d value Intensity Intensity % 2-Theta ° Angstrom Count % 7.91411.1617 1784 70 9.127 9.6809 658 26 10.524 8.3989 1830 72 13.118 6.74371517 59 14.764 5.9953 534 21 15.359 5.7642 1287 50 15.872 5.5792 727 2817.574 5.0424 542 21 18.352 4.8302 1102 43 19.634 4.5178 642 25 20.0764.4192 643 25 20.643 4.2992 510 20 21.136 4.1999 1911 75 21.512 4.1275597 23 22.158 4.0085 2561 100 22.759 3.9039 637 25 24.058 3.6960 479 1924.623 3.6124 349 14 25.323 3.5142 772 30 26.287 3.3875 552 22 26.9203.3092 437 17 27.360 3.2570 380 15 27.667 3.2215 765 30 28.217 3.1600413 16 29.736 3.0019 404 16The behavior of that solvate under heating has been monitored by usingTR-XRPD. FIG. 3B, which shows that after desolvation the solid could beidentified as form V.

EXAMPLE 4 Ethyl Acetate Solvate

In a vial, 0.50 g of the5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(crystallized as form VI) were dissolved in 1.15 g of ethyl acetate atroom temperature. The solid was completely dissolved into the solvent,and after 30 minutes, a solid recrystallized. The suspension wasfiltrated gently under vacuum with a glass filter (porosity 3). TheX-ray powder diffraction pattern of this powder is presented FIG. 4A.

TABLE 4 Characteristic XRPD peaks of maribavir Ethylacetate solvateAngle d value Intensity Intensity % 2-Theta ° Angstrom Count % 5.95514.8299 44556 100 10.596 8.3424 479 1 10.843 8.1524 646 1 11.917 7.4200962 2 13.632 6.4902 570 1 13.920 6.3567 443 1 14.933 5.9275 690 2 15.7035.6385 1465 3 15.993 5.5371 2174 5 17.956 4.9359 2507 6 18.360 4.82812541 6 19.038 4.6579 494 1 20.063 4.4222 1311 3 21.036 4.2197 385 121.508 4.1282 752 2 21.798 4.0738 644 1 22.573 3.9358 591 1 23.0953.8479 1072 2 23.639 3.7606 3992 9 23.992 3.7061 2348 5 25.643 3.4711366 1 26.100 3.4114 441 1 26.656 3.3414 347 1 28.167 3.1655 946 2 28.4373.1360 407 1

The behavior of that solvate under heating has been monitored by usingTR-XRPD. FIG. 4B shows the successive phases: the ethylacetatesolvate—form VII and form VI.

EXAMPLE 5 Diethyl Ether Solvate

In a vial, 0.54 g of the5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(crystallized as form VI) were dissolved in 8.0 g of diethyl ether at20° C. A suspension was obtained. After 16 days of stirring, the majorpart of the liquid was removed with a pipette. The remaining slurry wasanalyzed by X-ray powder diffraction (FIG. 5A).

TABLE 5 Characteristic XRPD peaks of maribavir diethylether solvateAngle d value Intensity Intensity % 2-Theta ° Angstrom Count % 6.03314.6380 3178 100 10.880 8.1250 1032 33 13.647 6.4831 728 23 14.1396.2588 804 25 15.109 5.8590 721 23 15.736 5.6268 623 20 16.442 5.38701217 38 16.844 5.2593 606 19 18.145 4.8850 1629 51 18.778 4.7216 1421 4519.140 4.6331 700 22 20.361 4.3581 608 19 21.164 4.1945 674 21 21.5974.1112 765 24 23.469 3.7875 542 17 23.741 3.7446 704 22 24.113 3.68781515 48 26.000 3.4243 465 15 28.941 3.0826 612 19The behavior of that solvate under heating has been monitored by usingTR-XRPD. FIG. 5B shows the transformation from diethylether solvate toform VII. It is expected that further heating would have led to thesolid-solid transformation into form VI.

EXAMPLE 6 n-Butyl Acetate Solvate

In a vial, 1.10 g of the5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(crystallized as form VI) were dissolved in 4.03 g of n-butyl acetate at20° C. A suspension was obtained. After 1 day of stirring, the majorpart of the liquid was removed with a pipette. The remaining slurry wasanalyzed by X-ray powder diffraction (FIG. 6).

TABLE 6 Characteristic XRPD peaks of maribavir n-butyl acetate solvateAngle d value Intensity Intensity % 2-Theta ° Angstrom Count % 5.90014.9685 1331 100 10.840 8.1547 761 57 11.702 7.5558 743 56 13.603 6.5039695 52 17.911 4.9482 814 61 18.300 4.8440 783 59 18.784 4.7203 780 5919.703 4.5022 754 57 20.580 4.3122 742 56 20.860 4.2549 753 57 21.6614.0994 726 55 21.983 4.0400 725 55 22.501 3.9481 792 60 22.996 3.8642863 65 23.460 3.7889 891 67 27.395 3.2530 715 54

EXAMPLE 7 1-Propanol Solvate

In a vial, 1.20 g of the5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(crystallized as form VI) were dissolved in 2.25 g of n-butyl acetate at0° C. A suspension was obtained. After 1 day of stirring, the major partof the liquid was removed with a pipette. The remaining slurry wasanalyzed by X-ray powder diffraction (FIG. 7).

TABLE 7 Characteristic XRPD peaks of maribavir 1-propanol solvate Angled value Intensity Intensity % 2-Theta ° Angstrom Count % 9.154 9.6530649 31 9.559 9.2443 2073 100 10.488 8.4282 748 36 11.204 7.8907 1193 5812.216 7.2392 619 30 14.025 6.3093 805 39 14.408 6.1423 642 31 16.0065.5328 644 31 17.796 4.9799 748 36 18.209 4.8678 749 36 18.926 4.68501094 53 20.917 4.2434 1995 96 21.200 4.1874 680 33 21.436 4.1419 680 3322.375 3.9702 658 32 23.024 3.8597 1454 70 23.402 3.7981 576 28 24.0313.7002 630 30 25.400 3.5037 607 29 25.892 3.4383 607 29 28.533 3.1257668 32 28.970 3.0796 1497 72

EXAMPLE 8 Hydrochloride Monohydrate

In a round bottom flask, 5.3250 g of the5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole(crystallized as form VI) were dissolved in 25 mL of concentratedaqueous hydrochloric acid at room temperature. The, the solution wascompletely evaporated under vacuum (T=40° C., P=28 mBar). A crystallinepowder was obtained. The X-ray powder diffraction pattern of this powderis presented FIG. 8A.

TABLE 8A Characteristic XRPD peaks of maribavir hydrochloridemonohydrate Experimental values Calculated values Angle d valueIntensity % Angle d value Intensity % 2-Theta ° Angstrom % 2-Theta °Angstrom % H k l 5,619 15,7141 23 5,612 15,7357 57 1 1 0 7,996 11,0484100 7,939 11,1268 100 2 0 0 8,921 9,9048 15 8,878 9,9521 36 2 1 0 11,2807,8375 4 11,237 7,8678 11 2 2 0 11,734 7,5355 3 11,724 7,5419 30 1 0 112,608 7,0149 2 12,568 7,0372 1 3 1 0 13,626 6,4933 1 13,603 6,5041 3 20 1 14,375 6,1565 5 14,339 6,172 90 3 2 0 15,939 5,5559 1 15,917 5,56341 4 0 0 16,75 5,2885 35 3 1 1 16,881 5,2479 14 16,89 5,2452 32 3 3 018,162 4,8806 1 18,125 4,8904 1 3 2 1 19,857 4,4676 7 19,814 4,4771 18 41 1 20,997 4,2274 8 20,996 4,2278 19 4 2 1 21,506 4,1285 6 21,486 4,132413 5 2 0 22,232 3,9954 2 22,16 4,0081 5 0 0 2 22,613 3,9289 12 22,5843,9339 22 4 4 0 22,842 3,8900 8 22,835 3,8912 8 5 0 1 22,835 3,8912 9 43 1 23,989 3,7066 3 23,915 3,7179 9 2 1 2 23,974 3,7089 1 6 0 0 24,9483,5662 5 24,911 3,5714 18 2 2 2 25,298 3,5176 11 25,235 3,5263 30 3 0 225,291 3,5186 5 6 2 0The single crystal analysis led to the following crystallographicparameter determination:

TABLE 8B Crystallographic parameters of Maribavir hydrochloridemonohydrate Crystal system Tetragonal Space group P4₂2₁2 Z 8 Z′ 1 a (Å)22.25 b (Å) 22.25 c (Å) 8.016 V (Å³) 3969.8 Dcalc. (g · cm⁻³) 1.465The behavior of that solvate under heating has been monitored by usingTGA-DSC. FIG. 8B shows the dehydration of the compound, together withthe melting of the newly formed anhydrous form.

EXAMPLE 9

Single crystals were obtained from a slow evaporation of the an ethylacetate solution of maribavir at 323 K. This temperature above theperitectic transition of the ethylacetate solvate allows the directioncrystallization of (the non solvated) Form VI.

A melting point of 469.5 K and a fusion enthalpy of 83.3 J/g weredetermined from DSC studies.

TABLE 9A Crystallographic parameters, single crystal X-ray diffractiondata collection and resolution data Crystal data C₁₅H₁₉Cl₂N₃O₄ Mo Kαradiation Mr = 376.23 λ = 0.71073 Å Tetragonal Space group: P4₁2₁2 a =9.2852 (4) Å μ = 0.386 mm−1 c = 41.602 (2) Å T = 296 (2) K V = 3586.7(3) Å³ Prismatic Z = 8 Colorless D_(x) = 1.393 Mg m⁻³ 0.5 × 0.15 × 0.15mm D_(m) not measured Data collection CCD area detector diffractometer3506 reflections with Phi and ω scans >2sigma(I) Absorption correction:R_(int) = 0.0239 Multi-scan sadabs (Sheldrich, θ_(max) = 26.38° Bruker,2000) H = −11 → 11 K = −11 → 11 28832 measured reflections L = −51 → 513678 independent reflections R[F² > 2o' (F²)] = 0.0404 Δ_(ρmax) = 0.275e Å⁻³ wR(F2_= 0.1071 Δ_(pmin) = −0.183 e Å⁻³ S = 1.084 Extinctioncorrection: none 3678 reflections Scattering factors from InternationalTables for Crystallography (Vol. C) H atoms treated by a mixture ofAbsolute structure: Flack H D independent and constrained (1983), ActaCryst. A39, refinement 876-881 W = I/o'²(F_(o) ²) + (0.0603P)² +0.8608P] Flack parameter = −0.02 (7) where P = F_(o) ² + 2F_(c) ²)/3

TABLE 9B Intramolecular H-bonds (Å, °) D—H . . . A D—H H . . . A D . . .A D—H . . . A O3—H3O . . . O4 0.820 2.136 2.627 118.34 N2—H2N . . . O20.901 2.109 2.979 161.92 N2—H2N . . . O1 0.901 2.383 2.934 119.53

TABLE 9C Intermolecular H-bonds (Å, °) D—H . . . A D—H H . . . A D . . .A D—H . . . A O2—H3O . . . O3 0.820 2.126 2.942 173.38 O4—H4O . . . N10.801 1.937 2.736 175.06 O3—H3O . . . Cl2 0.820 2.771 3.247 118.81O3—H3O . . . Cl1 0.820 2.965 3.695 149.59Anisotropic displacement parameters were refined for non-H atoms. H4Oand H2N atoms were located from subsequent Fourier difference synthesesand refined isotropically. All the other H atom positions werecalculated.

An ORTEP drawing of the asymmetric unit of Form VI was determined (asshown in FIG. 9).

The fractional coordinates of the atoms in form VI are listed in table9D below:

TABLE 9D Fractional coordinates of the atoms in Form VI (for Example 9)atom Label Atom type x/a y/b z/c Cl1 Cl 1.38082(7) 0.89331(8)0.091947(16) Cl2 Cl 1.23358(8) 1.11972(9) 0.045202(15) O1 O 0.92486(18)0.94130(18) 0.22053(3) N3 N 0.9405(2) 0.9974(2) 0.16604(4) O4 O0.8751(2) 0.6661(2) 0.16268(4) N1 N 0.8384(2) 1.1596(2) 0.13264(5) C5 C1.0305(2) 1.0074(2) 0.13922(5) O3 O 0.9270(2) 0.5895(2) 0.22234(4) H3O H0.9706 0.5805 0.2053 C6 C 1.1575(2) 0.9403(3) 0.13157(5) H6 H 1.19940.8727 0.1452 C7 C 0.8261(2) 1.0910(3) 0.16033(5) C11 C 0.9465(2)0.8826(2) 0.18960(4) H11 H 1.0418 0.8373 0.1888 C14 C 0.8324(2)0.7676(3) 0.18575(5) H14 H 0.7399 0.8109 0.1798 C13 C 0.8250(3)0.7035(3) 0.21955(6) H13 H 0.7275 0.6694 0.2244 C1 C 1.2208(2) 0.9784(3)0.10236(5) C12 C 0.8663(2) 0.8297(3) 0.24125(5) H12 H 0.9416 0.79800.2562 N2 N 0.7199(3) 1.1065(3) 0.18153(5) C3 C 1.0294(3) 1.1449(3)0.09021(5) H3 H 0.9875 1.2121 0.0765 C8 C 0.5993(3) 1.2057(3) 0.17685(6)H8 H 0.6158 1.2633 0.1575 C4 C 0.9651(2) 1.1087(3) 0.11920(5) C2 C1.1576(2) 1.0781(3) 0.08223(5) C9 C 0.5898(6) 1.3039(5) 0.20568(11) H9AH 0.5748 1.2474 0.2247 H9B H 0.5108 1.3694 0.2030 H9C H 0.6778 1.35740.2077 C10 C 0.4649(5) 1.1212(6) 0.17310(14) H10A H 0.4749 1.0561 0.1553H10B H 0.3858 1.1853 0.1692 H10C H 0.4471 1.0673 0.1924 C15 C 0.7453(3)0.8940(3) 0.26021(5) H15A H 0.7098 0.8249 0.2758 H15B H 0.7786 0.97870.2717 O2 O 0.6337(2) 0.9323(2) 0.23849(4) H2O H 0.5665 0.9680 0.2485.H2N H 0.714(3) 1.056(3) 0.2000(7) H4O H 0.814(4) 0.669(4) 0.1492(10).Data collection: Bruker SMART. Cell refinement: Bruker SMART. Datareduction: Bruker SAINT. Program(s) used to solve structure: SHELXS-97(Sheldrick, 1990). Program(s) used to refine structure: SHELXL97(Sheldrick, 1997). Molecular graphics: diamond (Brandenburg and Berndt,1999). Software used to prepare material for publication: SHELXS-97 andPLATON (Speck, 2003).

A number of patent and non-patent documents are cited in the foregoingspecification in order to describe the state of the art to which thisinvention pertains. The entire disclosure of each of these citations isincorporated by reference herein.

While various embodiments of the present invention have been describedand/or exemplified above, numerous other embodiments will be apparent tothose skilled in the art upon review of the foregoing disclosure. Thepresent invention is, therefore, not limited to the particularembodiments described and/or exemplified, but is capable of considerablevariations and modifications without departure from the scope of theappended claims. Furthermore, the transitional phrases “comprising”,“consisting essentially of” and “consisting of” define the scope of theappended claims, in original and amended form, with respect to whatunrecited additional claim elements or steps. The term “comprising” isintended to be inclusive or open-ended and does not exclude additional,unrecited elements, methods step or materials. The phrase “consistingof” excludes any element, step or material other than those specified inthe claim, and, in the latter instance, impurities ordinarily associatedwith the specified materials. The phrase “consisting essentially of”limits the scope of a claim to the specified elements, steps ormaterials and those that do not materially affect the basic and novelcharacteristic(s) of the claimed invention. All compositions orformulations identified herein can, in alternate embodiments, be morespecifically defined by any of the transitional phases “comprising”,“consisting essentially of” and “consisting of”.

REFERENCES

-   1. Brandenburg, K. (2001), Diamond version 2. 1, Crystal Impact,    Gbr;-   2. Bruker (2001). SMART. Version 5.622. Bruker AXS Inc., Madison,    Wis., USA-   3. Bruker (1999). SAINT. Version 5.6.0 Bruker AXS Inc., Madison,    Wis., USA-   4. Flack, H. D. (1986), Acta Cryst., A39, 876-881-   5. Sheldrick, G. M. (1997). SHELXTL. Version 6.10 Bruker AXS Inc.,    Madison, Wis., USA-   6. Sheldrick, G. M. (2001). SADABS, University of Gottingen,    Germany;-   7. U.S. Pat. No. 6,077,832 to Chamberlain et al.-   8. U.S. Pat. No. 6,469,160 to Glover et al.-   9. U.S. Pat. No. 6,482,939 to Hodson and Huang

The invention relates to the novel unsolvated crystalline forms andsolvates described herein, both in pure form and in admixture with othersuch polymorphs and/or known forms or solvates of the compound offormula (I), above. For example, the admixture may include thecombinations listed in Table 10 below.

TABLE 10 List of crystalline phase admixtures of maribavir: Component 3Component 1 Component 2 (Optional) Form VI Form VII One or more othersolid phases of maribavir. Form VI methanol solvate One or more othersolid phases of maribavir. Form VI acetonitrile solvate One or moreother solid phases of maribavir. Form VI ethyl acetate solvate One ormore other solid phases of maribavir. From VI diethyl ether solvate Oneor more other solid phases of maribavir. Form VI n-butyl acetate solvateOne or more other solid phases of maribavir. Form VI 1-propanol solvateOne or more other solid phases of maribavir. Form VI monohydratehydrochloride One or more other solid phases of maribavir.

What is claimed is:
 1. A crystalline solvate of5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole,including a stoichiometric ratio of an organic solvent within a cavityof the crystal lattice, said solvent being selected from the group of:methanol, acetonitrile, ethyl acetate, diethylether, n-butylacetate, or1-propanol, or mixtures thereof.
 2. Crystalline Form VI of5,6-dichloro-2-(isopropylamino)-1-(β-L-ribofuranosyl)-1H-benzimidazole,wherein said compound has unit cell parameters a=b=9.2825 Å, c=41.602 Å,and P4₁2₁2 space group (recorded at 296 K).